During the growth of bacterial quorum, bacteria can generate chemical signaling molecules (also called auto inducers) ceaselessly and these signaling molecules are subsequently secreted in the extracellular environment. When the concentration of the signaling molecules reaches a threshold, the expression of relevant genes in bacteria, such as genes related with bioluminescence, formation of biofilms and virulence, is regulated or activated to adapt to the environmental changes. Such a regulatory system is known as bacterial quorum sensing (QS) system.
QS system was first observed in V. fischeri. When the density of bacteria was high, the bacteria luminesce so as to catch food, avoid predators, etc. It is found by studying on its mechanism that, in V. fischeri, N-acyl homoserine lactones (AHL) synthesized by Luxi protein can bind to N-terminal of AHL receptor protein encoded by LuxR and form a specific configuration to enable the binding of C-terminal of AHL receptor protein to the target DNA sequence, thereby activating the transcription and expression of illuminant gene. Similar regulatory systems were found in many Gram-positive or Gram-negative bacteria. Their mechanism resides in that when bacteria are at a low population density, little autoinducer is produced, the inducer is diffused extracellularly and diluted immediately in the surrounding environment. When the population density of bacteria increases gradually and reaches a threshold, the signaling molecules will permeate into cells and bind to the corresponding transcriptional regulatory protein to form a transcriptional regulatory protein-signaling molecule polymer, which can bind to a specific DNA sequence encoding the signaling molecule in chromosome and enables the expression of relevant target gene, resulting in the production of more signaling molecules. Such communication and transduction of information among bacteria have been proposed for a long time. However, systematic research is only conducted in the recent 10 years. Such a phenomenon has been demonstrated in many bacteria now.
In the late 1970s, scientists found that naturally occurring or artificially synthesized bacterial quorum-sensing regulators (including agonists or inhibitors) can interfere with the transduction of signaling system and regulate the expression of virulence gene in bacteria. Bacterial quorum-sensing regulators deprive pathogenic bacteria of pathogenic ability by regulating the expression of its virulence gene, without interfering with normal physiological functions of cells in vivo, thus are regarded as a new direction for the development of antibacterials. Bacterial quorum-sensing inhibitors can be used in combination with antibiotics to enhance sensitivity of pathogenic bacteria to antibiotics so as to improve therapeutic effect of drugs, and can be used to treat various diseases caused by Gram-negative bacteria such as endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, pyothorax, and sepsis.
The object of the invention is to find out new bacterial quorum-sensing regulators for use in the prevention and/or treatment of a disease caused by a Gram-negative bacterium, particularly a disease caused by a drug-resistant Gram-negative bacterium.